Systemic and Proximal Tubule Specific Knockout of Arhgef11 and Impact on Hypertension and Kidney Injury

Hypertension is a progressive condition that predisposes patients to the development of chronic kidney disease (CKD). Previous genetic and animal studies utilizing the Dahl salt-sensitive (SS) rat, a genetic model of progressive hypertension and CKD, identified that Arhgef11 was playing a role in hypertension and CKD in the Dahl SS model. Arhgef11 is a Rho guanine nucleotide exchange factor involved in the regulation of the cytoskeleton, intracellular trafficking, protein-protein interactions, and transcription factor regulation. Temporal evaluation of SS-wild type (WT) and SS-Arhgef11-/- rats demonstrated that the loss of Arhgef11 attenuated hypertension and improved renal function. Transcriptome and proteomic studies lead to the hypothesis that dysregulation of these pathways in the kidney, particularly the proximal tubule, may alter sodium handling and ultimately lead to hypertension. Current rat studies confirmed previous work between SS-WT and SS-Arhgef11-/- and investigated early (week 4) transcriptional changes using single-nuclei RNA sequencing, present before blood pressure differences are observed. Due to only being able to test systemic loss of Arhgef11 in the rat model, a global knockout [Arhgef11-/-(CMV)], as well as a proximal tubule-specific deletion [Arhgef11-/-(Sglt2)] were studied in the mouse. Studies utilized two models of experimental hypertension: Angiotensin II and deoxycorticosterone acetate (DOCA) + salt. Both models demonstrated a slight protective effect on blood pressure and kidney injury for DOCA experimental models, replicating the rat knockout data. However, the impact of the loss of Arhgef11 was dependent on the type of induced hypertension, with the large effect in the rat model likely explained by the highly permissive genetic background of the Dahl SS model.NEW & NOTEWORTHY The present study tests the hypothesis that Arhgef11, specifically within the context of experimental hypertension (AngII or DOCA), plays a role in regulating blood pressure at the systemic or kidney-specific level. A slight protective effect on blood pressure and kidney injury for DOCA knockout models was observed, replicating the rat knockout. However, the large effect in the rat model is likely explained by the highly permissive genetic background of the Dahl SS model.